tbuckley/cabot-search huggingface dataset:
FABP4 in Paneth cells regulates antimicrobial protein expression to reprogram gut microbiota
Authors: Xiaomin Su, Mengli Jin, Chen Xu, Yunhuan Gao, Yazheng Yang, Houbao Qi, Qianjing Zhang, Xiaorong Yang, Wang Ya, Yuan Zhang, Rongcun Yang
Journal: Gut Microbes (2022)

Antimicrobial proteins possess a broad spectrum of bactericidal activity and play an important role in shaping the composition of gut microbiota, which is related to multiple diseases such as metabolic syndrome. However, it is incompletely known for the regulation of defensin expression in the gut Paneth cells. Here, we found that FABP4 in the Paneth cells of gut epithelial cells and organoids can downregulate the expression of defensins. FABP4fl/flpvillinCreT mice were highly resistance to Salmonella Typhimurium (S.T) infection and had increased bactericidal ability to pathogens. The FABP4-mediated downregulation of defensins is through degrading PPARγ after K48 ubiquitination. We also demonstrate that high-fat diet (HFD)-mediated downregulation of defensins is through inducing a robust FABP4 in Paneth cells. Firmicutes/Bacteroidetes (F/B) ratio in FABP4fl/flpvillinCreT mice is lower than control mice, which is opposite to that in mice fed HFD, indicating that FABP4 in the Paneth cells could reprogram gut microbiota. Interestingly, FABP4-mediated downregulation of defensins in Paneth cells not only happens in mice but also in human. A better understanding of the regulation of defensins, especially HFD-mediated downregulation of defensin in Paneth cells will provide insights into factor(s) underlying modern diseases.Abbreviations: FABP4: Fatty acid binding protein 4; S. T: Salmonella Typhimurium; HFD: High-fat diet; Defa: α-defensin; 930 HD5: Human α-defensin 5; HD6: Human α-defensin 6; F/B: Firmicutes/Bacteroidetes; SFB: Segmental filamentous bacteria; AMPs: Antimicrobial peptides; PPARγ: Peroxisome proliferator-activated receptor γ; P-PPAR: Phosphorylated PPAR; Dhx15: DEAD-box helicase 15; 935 EGF: Epidermal growth factor; ENR: Noggin and R-spondin 1; CFU: Colony forming unit; Lyz1: Lysozyme 1; Saa1: Serum amyoid A 1; Pla2g2a: Phospholipase A2, group IIA; MMP-7: Matrix metalloproteinase; AU-PAGE: Acid-urea polyacrylamide gel electrophoresis; PA: Palmitic 940 acid; GPR40: G-protein-coupled receptor; GF: Germ-free; EGF: Epidermal growth factor; LP: Lamina propria; KO: Knock out; WT: Wild-type.
Artificial intelligence-based personalized diet: A pilot clinical study for irritable bowel syndrome
Authors: Tarkan Karakan, Aycan Gundogdu, Hakan Alagözlü, Nergiz Ekmen, Seckin Ozgul, Varol Tunali, Mehmet Hora, Damla Beyazgul, O. Ufuk Nalbantoglu
Journal: Gut Microbes (2022)

We enrolled consecutive IBS-M patients (n = 25) according to Rome IV criteria. Fecal samples were obtained from all patients twice (pre-and post-intervention) and high-throughput 16S rRNA sequencing was performed. Six weeks of personalized nutrition diet (n = 14) for group 1 and a standard IBS diet (n = 11) for group 2 were followed. AI-based diet was designed based on optimizing a personalized nutritional strategy by an algorithm regarding individual gut microbiome features. The IBS-SSS evaluation for pre- and post-intervention exhibited significant improvement (p &lt; .02 and p &lt; .001 for the standard IBS diet and personalized nutrition groups, respectively). While the IBS-SSS evaluation changed to moderate from severe in 78% (11 out of 14) of the personalized nutrition group, no such change was observed in the standard IBS diet group. A statistically significant increase in the Faecalibacterium genus was observed in the personalized nutrition group (p = .04). Bacteroides and putatively probiotic genus Propionibacterium were increased in the personalized nutrition group. The change (delta) values in IBS-SSS scores (before-after) in personalized nutrition and standard IBS diet groups are significantly higher in the personalized nutrition group. AI-based personalized microbiome modulation through diet significantly improves IBS-related symptoms in patients with IBS-M. Further large-scale, randomized placebo-controlled trials with long-term follow-up (durability) are needed.
P38 kinases mediate NLRP1 inflammasome activation after ribotoxic stress response and virus infection
Authors: Lea-Marie Jenster, Karl-Elmar Lange, Sabine Normann, Anja vom Hemdt, Jennifer D. Wuerth, Lisa D.J. Schiffelers, Yonas M. Tesfamariam, Florian N. Gohr, Laura Klein, Ines H. Kaltheuner, Stefan Ebner, Dorothee J. Lapp, Jacob Mayer, Jonas Moecking, Hidde L. Ploegh, Eicke Latz, Felix Meissner, Matthias Geyer, Beate M. Kümmerer, Florian I. Schmidt
Journal: The Journal of Experimental Medicine (2022)

Inflammasomes integrate cytosolic evidence of infection or damage to mount inflammatory responses. The inflammasome sensor NLRP1 is expressed in human keratinocytes and coordinates inflammation in the skin. We found that diverse stress signals induce human NLRP1 inflammasome assembly by activating MAP kinase p38: While the ribotoxic stress response to UV and microbial molecules exclusively activates p38 through MAP3K ZAKα, infection with arthropod-borne alphaviruses, including Semliki Forest and Chikungunya virus, activates p38 through ZAKα and potentially other MAP3K. We demonstrate that p38 directly phosphorylates NLRP1 and that serine 107 in the linker region is critical for activation. NLRP1 phosphorylation is followed by ubiquitination of NLRP1PYD, N-terminal degradation of NLRP1, and nucleation of inflammasomes by NLRP1UPA-CARD. In contrast, activation of NLRP1 by nanobody-mediated ubiquitination, viral proteases, or inhibition of DPP9 was independent of p38 activity. Taken together, we define p38 activation as a unifying signaling hub that controls NLRP1 inflammasome activation by integrating a variety of cellular stress signals relevant to the skin.
Complexity and Challenges of the Clinical Diagnosis and Management of Long COVID
Authors: Ann M. O’Hare, Elizabeth K. Vig, Theodore J. Iwashyna, Alexandra Fox, Janelle S. Taylor, Elizabeth M. Viglianti, Catherine R. Butler, Kelly C. Vranas, Mark Helfand, Anaïs Tuepker, Shannon M. Nugent, Kara A. Winchell, Ryan J. Laundry, C. Barrett Bowling, Denise M. Hynes, Matthew L. Maciejewski, Amy S. B. Bohnert, Emily R. Locke, Edward J. Boyko, George N. Ioannou
Journal: JAMA Network Open (2022)

Importance There is increasing recognition of the long-term health effects of SARS-CoV-2 infection (sometimes called long COVID ). However, little is yet known about the clinical diagnosis and management of long COVID within health systems. Objective To describe dominant themes pertaining to the clinical diagnosis and management of long COVID in the electronic health records (EHRs) of patients with a diagnostic code for this condition ( International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ ICD-10 ] code U09.9). Design, Setting, and Participants This qualitative analysis used data from EHRs of a national random sample of 200 patients receiving care in the Department of Veterans Affairs (VA) with documentation of a positive result on a polymerase chain reaction (PCR) test for SARS-CoV-2 between February 27, 2020, and December 31, 2021, and an ICD-10 diagnostic code for long COVID between October 1, 2021, when the code was implemented, and March 1, 2022. Data were analyzed from February 5 to May 31, 2022. Main Outcomes and Measures A text word search and qualitative analysis of patients’ VA-wide EHRs was performed to identify dominant themes pertaining to the clinical diagnosis and management of long COVID. Results In this qualitative analysis of documentation in the VA-wide EHR, the mean (SD) age of the 200 sampled patients at the time of their first positive PCR test result for SARS-CoV-2 in VA records was 60 (14.5) years. The sample included 173 (86.5%) men; 45 individuals (22.5%) were identified as Black and 136 individuals (68.0%) were identified as White. In qualitative analysis of documentation pertaining to long COVID in patients’ EHRs 2 dominant themes were identified: (1) clinical uncertainty, in that it was often unclear whether particular symptoms could be attributed to long COVID, given the medical complexity and functional limitations of many patients and absence of specific markers for this condition, which could lead to ongoing monitoring, diagnostic testing, and specialist referral; and (2) care fragmentation, describing how post–COVID-19 care processes were often siloed from and poorly coordinated with other aspects of care and could be burdensome to patients. Conclusions and Relevance This qualitative study of documentation in the VA EHR highlights the complexity of diagnosing long COVID in clinical settings and the challenges of caring for patients who have or are suspected of having this condition.
FRACTION-RCC: nivolumab plus ipilimumab for advanced renal cell carcinoma after progression on immuno-oncology therapy
Authors: Toni K Choueiri, Harriet Kluger, Saby George, Scott S Tykodi, Timothy M Kuzel, Ruth Perets, Suresh Nair, Giuseppe Procopio, Michael A Carducci, Vincent Castonguay, Edmund Folefac, Chung-Han Lee, Sebastien J. Hotte, Wilson H Miller,, Shruti Shally Saggi, Chung-Wei Lee, Heshani Desilva, Prabhu Bhagavatheeswaran, Robert J Motzer, Bernard Escudier
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background The role and sequencing of combination immuno-oncology (IO) therapy following progression on or after first-line IO therapy has not been well-established. The Fast Real-time Assessment of Combination Therapies in Immuno-ONcology (FRACTION) program is an open-label, phase 2 platform trial designed to evaluate multiple IO combinations in patients with advanced renal cell carcinoma (aRCC) who progressed during or after prior IO therapy. Here, we describe the results for patients treated with nivolumab plus ipilimumab. For enrollment in track 2 (reported here), patients with histologically confirmed clear cell aRCC, Karnofsky performance status ≥70%, and life expectancy ≥3 months who had previously progressed after IO (anti-programmed death 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), or anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4)) therapy were eligible. Previous treatment with anti-CTLA-4 therapy plus anti-PD-1/PD-L1 therapy precluded eligibility for enrollment in the nivolumab plus ipilimumab arm. Patients were treated with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses, followed by nivolumab 480 mg every 4 weeks for up to 2 years or until progression, toxicity, or protocol-specified discontinuation. The primary outcome measures were objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS) rate at 24 weeks. Secondary outcomes were safety and tolerability up to 2 years. Overall survival (OS) was a tertiary/exploratory endpoint. Overall, 46 patients were included with a median follow-up of 33.8 months. The ORR was 17.4% (95% CI, 7.8 to 31.4) with eight (17.4%) patients achieving partial response. Stable disease was achieved in 19 (41.3%) patients, while 14 (30.4%) had progressive disease. Median DOR (range) was 16.4 (2.1+ to 27.0+) months. The PFS rate at 24 weeks was 43.2%, and median OS was 23.8 (95% CI, 13.2 to not reached) months. Grade 3–4 immune-mediated adverse events were reported in seven (15.2%) patients. No treatment-related deaths were reported. Patients with aRCC treated with nivolumab plus ipilimumab may derive durable clinical benefit after progression on previous IO therapies, including heavily pretreated patients, with a manageable safety profile that was consistent with previously published safety outcomes. These outcomes contribute to the knowledge of optimal sequencing of IO therapies for patients with aRCC with high unmet needs. Trial registration number NCT02996110 .
Fracture Risk Among Older Cancer Survivors Compared With Older Adults Without a History of Cancer
Authors: Erika Rees-Punia, Christina C. Newton, Helen M. Parsons, Corinne R. Leach, W. Ryan Diver, Amber C. Grant, Matthew Masters, Alpa V. Patel, Lauren R. Teras
Journal: JAMA Oncology (2022)

The number of cancer survivors living in the US is projected to be 26.1 million by 2040. Cancer survivors may be at increased risk of bone fractures, but research is limited in several important ways.To investigate the associations of cancer diagnoses, including time since diagnosis and stage at diagnosis, with risks of pelvic, radial, and vertebral fractures (separately and combined) among older cancer survivors and compared with fracture risk among older adults without a history of cancer. Secondarily, to examine differences in risk of fracture stratified by modifiable behaviors, treatment, and cancer type.This longitudinal cohort study used data from 92 431 older adults in the US Cancer Prevention Study II Nutrition Cohort linked with 1999 to 2017 Medicare claims. Data were analyzed from July 15, 2021, to May 3, 2022.Cancer history, time since cancer diagnosis, and stage at cancer diagnosis.Hazard ratios (HRs) and 95% CIs for the risk of pelvic, radial, vertebral, and total frailty-related fractures were estimated using multivariate Cox proportional hazards regression. Stratification was used for secondary aims.Among 92 431 participants (mean [SD] age, was 69.4 [6.0] years, 51 820 [56%] women, and 90 458 [97.9%] White], 12 943 participants experienced a frailty-related bone fracture. Compared with participants without a history of cancer, cancer survivors who were diagnosed 1 to less than 5 years earlier with advanced stage cancer had higher risk of fracture (HR, 2.12; 95% CI, 1.75-2.58). The higher fracture risk in cancer survivors with recent advanced stage diagnosis (vs no cancer) was driven largely by vertebral (HR, 2.46; 95% CI, 1.93-3.13) and pelvic (HR, 2.46; 95% CI, 1.84-3.29) fracture sites. Compared with cancer survivors who did not receive chemotherapy, survivors who received chemotherapy were more likely to have a fracture; this association was stronger within 5 years of diagnosis (HR, 1.31; 95% CI, 1.09-1.57) than 5 or more years after diagnosis (HR, 1.22; 95% CI, 0.99-1.51). Although the HR for risk of fracture was lower among physically active cancer survivors 5 or more years after diagnosis (HR, 0.76; 95% CI, 0.54-1.07), this result was not statistically significant, whereas current smoking was significantly associated with higher risk of fracture (HR, 2.27; 95% CI, 1.55-3.33).Findings from this cohort study suggest that older adults with a history of cancer may benefit from clinical guidance on prevention of frailty-related fractures. If study findings are replicated, fracture prevention programs for survivors might include referrals for physical activity with cancer exercise professionals and smoking cessation programs.
Youth-onset type 2 diabetes mellitus: an urgent challenge
Authors: Petter Bjornstad, Lily C. Chao, Melanie Cree-Green, Allison B. Dart, Malcolm King, Helen C. Looker, Dianna J. Magliano, Kristen J. Nadeau, Orit Pinhas-Hamiel, Amy S. Shah, Daniel H. van Raalte, Meda E. Pavkov, Robert G. Nelson
Journal: Nature Reviews Nephrology (2022)
Self-reporting of Conflicts of Interest by Ophthalmology Researchers Compared with the Open Payments Database Industry Reports
Authors: Eileen S. Hwang, Lawrence Liu, Meng-Yung Ong, Clair M. Rodriguez, Devin E. Schwehr, David E. Sanchez, Gregory J. Stoddard, David V. Weinberg
Journal: Ophthalmology (2022)
Assessment of Iris Trabecular Contact in Eyes with Gonioscopic Angle-Closure
Authors: Xiulan Zhang, Philip Yawen Guo, Chen Lin, Fei Li, Anwell Nguyen, Rei Sakata, Risa Higashita, Keiichiro Okamoto, Marco Yu, Makoto Aihara, Tin Aung, Shan Lin, Christopher Kai-shun Leung
Journal: Ophthalmology (2022)
Inhibitory Kcnip2 neurons of the spinal dorsal horn control behavioral sensitivity to environmental cold
Authors: Gioele W. Albisetti, Robert P. Ganley, Francesca Pietrafesa, Karolina Werynska, Marília Magalhaes de Sousa, Rebecca Sipione, Louis Scheurer, Michael R. Bösl, Pawel Pelczar, Hendrik Wildner, Hanns Ulrich Zeilhofer
Journal: Neuron (2022)

Proper sensing of ambient temperature is of utmost importance for the survival of euthermic animals, including humans. While considerable progress has been made in our understanding of temperature sensors and transduction mechanisms, the higher-order neural circuits processing such information are still only incompletely understood. Using intersectional genetics in combination with circuit tracing and functional neuron manipulation, we identified Kcnip2-expressing inhibitory (Kcnip2GlyT2) interneurons of the mouse spinal dorsal horn as critical elements of a neural circuit that tunes sensitivity to cold. Diphtheria toxin-mediated ablation of these neurons increased cold sensitivity without affecting responses to other somatosensory modalities, while their chemogenetic activation reduced cold and also heat sensitivity. We also show that Kcnip2GlyT2 neurons become activated preferentially upon exposure to cold temperatures and subsequently inhibit spinal nociceptive output neurons that project to the lateral parabrachial nucleus. Our results thus identify a hitherto unknown spinal circuit that tunes cold sensitivity.
Routine Vaccination Coverage — Worldwide, 2021
Authors: Audrey Rachlin, M. Carolina Danovaro-Holliday, Padraic Murphy, Samir V. Sodha, Aaron S. Wallace
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

In 2020, the World Health Assembly endorsed the Immunization Agenda 2030, an ambitious global immunization strategy to reduce morbidity and mortality from vaccine-preventable diseases (1). This report updates a 2020 report (2) with global, regional,* and national vaccination coverage estimates and trends through 2021. Global estimates of coverage with 3 doses of diphtheria-tetanus-pertussis-containing vaccine (DTPcv3) decreased from an average of 86% during 2015-2019 to 83% in 2020 and 81% in 2021. Worldwide in 2021, 25.0 million infants (19% of the target population) were not vaccinated with DTPcv3, 2.1 million more than in 2020 and 5.9 million more than in 2019. In 2021, the number of infants who did not receive any DTPcv dose by age 12 months (18.2 million) was 37% higher than in 2019 (13.3 million). Coverage with the first dose of measles-containing vaccine (MCV1) decreased from an average of 85% during 2015-2019 to 84% in 2020 and 81% in 2021. These are the lowest coverage levels for DTPcv3 and MCV1 since 2008. ​Global coverage estimates were also lower in 2021 than in 2020 and 2019 for bacillus Calmette-Guérin vaccine (BCG) as well as for the completed series of Haemophilus influenzae type b vaccine (Hib), hepatitis B vaccine (HepB), polio vaccine (Pol), and rubella-containing vaccine (RCV). The COVID-19 pandemic has resulted in disruptions to routine immunization services worldwide. Full recovery to immunization programs will require context-specific strategies to address immunization gaps by catching up missed children, prioritizing essential health services, and strengthening immunization programs to prevent outbreaks (3).
Prevalence and Characteristics of Arthritis Among Caregivers — 17 States, 2017 and 2019
Authors: Eva M.J. Jackson, John D. Omura, Michael A. Boring, Erica L. Odom, Anika L. Foster, Benjamin S. Olivari, Lisa C. McGuire, Janet B. Croft
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

Caregiving provides numerous benefits to both caregivers and care recipients; however, it can also negatively affect caregivers' mental and physical health (1-4), and caregiving tasks often require physical exertion (1). Approximately 44% of adults with arthritis report limitations attributable to arthritis, including trouble doing daily activities (5). These limitations might affect caregivers' ability to provide care, but little is known about arthritis among caregivers. To assess arthritis among caregivers of a family member or friend, CDC examined data from 17 states that administered both the arthritis and caregiving modules as part of the Behavioral Risk Factor Surveillance System (BRFSS) in either 2017 or 2019. Approximately one in five adults (20.6%) was a caregiver. Prevalence of arthritis was higher among caregivers (35.1%) than noncaregivers (24.5%). Compared with caregivers without arthritis, those with arthritis provided similar types of care and were more likely to have provided care for ≥5 years and for ≥40 hours per week. In addition, higher proportions of caregivers with arthritis reported disabilities compared with those without arthritis, including mobility issues (38.0% versus 7.3%). Arthritis among caregivers might affect their own health as well as the care they can provide. Caregivers can discuss their arthritis and related limitations with a health care professional to identify ways to increase their physical activity and participation in lifestyle management programs.* Such interventions might ease arthritis pain and related limitations and might support them in their ongoing caregiving role. Public health professionals can implement strategies to support caregivers throughout the caregiving process.†.
SegPC-2021: A challenge &amp; dataset on segmentation of Multiple Myeloma plasma cells from microscopic images
Authors: Anubha Gupta, Shiv Gehlot, Shubham Goswami, Sachin Motwani, Ritu Gupta, Álvaro García Faura, Dejan Štepec, Tomaž Martinčič, Reza Azad, Dorit Merhof, Afshin Bozorgpour, Babak Azad, Alaa Sulaiman, Deepanshu Pandey, Pradyumna Gupta, Sumit Bhattacharya, Aman Sinha, Rohit Agarwal, Xinyun Qiu, Yucheng Zhang, Ming Fan, Yoonbeom Park, Daehong Lee, Joon Sik Park, Kwangyeol Lee, Jaehyung Ye
Journal: Medical Image Analysis (2022)
The oxidative phosphorylation inhibitor IM156 suppresses B-cell activation by regulating mitochondrial membrane potential and contributes to the mitigation of systemic lupus erythematosus
Authors: Joo Sung Shim, Eun Jee Kim, Lucy Eunju Lee, Joon Ye Kim, Yuri Cho, Hanna Kim, Jieun Kim, Sung Hoon Jang, Jimin Son, Jae-Ho Cheong, Aekyong Kim, Beom Jin Lim, Sang-Jun Ha, Jason Jungsik Song, Beom Seok Kim
Journal: Kidney International (2022)
Mechanosensitive brain tumor cells construct blood-tumor barrier to mask chemosensitivity
Authors: Xin Chen, Ali Momin, Siyi Wanggou, Xian Wang, Hyun-Kee Min, Wenkun Dou, Zheyuan Gong, Jade Chan, Weifan Dong, Jerry J. Fan, Yi Xiong, Kamilia Talipova, Hongyu Zhao, Yuki X. Chen, Kelly Veerasammy, Adam Fekete, Sachin A. Kumar, Hongwei Liu, Qi Yang, Joe Eun Son, Zhengchao Dou, Malini Hu, Parnian Pardis, Kyle Juraschka, Laura K. Donovan, Jiao Zhang, Vijay Ramaswamy, Hayden J. Selvadurai, Peter B. Dirks, Michael D. Taylor, Lu-Yang Wang, Chi-chung Hui, Rinat Abzalimov, Ye He, Yu Sun, Xuejun Li, Xi Huang
Journal: Neuron (2022)
Synonymous mutations in TLR2 and TLR9 genes decrease COPD susceptibility in the Chinese Han population
Authors: X. Ding, Q. Lin, J. Zhao, Y. Fu, Y. Zheng, R. Mo, L. Zhang, B. Zhang, J. Chen, T. Xie, H. Wu, Y. Ding
Journal: Pulmonology (2022)

Previous studies have found associations between polymorphisms in some candidate genes and chronic obstructive pulmonary disease (COPD) risk. However, the association between TLR2 and TLR9 polymorphisms and COPD risk remains uncertain. Four variants (rs352140, rs3804099, rs3804100, and rs5743705) of the TLR2 and TLR9 genes in 540 COPD patients and 507 healthy controls were genotyped using the Agena MassARRAY system. Odds ratio (OR) and 95% confidence interval (CI) were calculated to assess the association of TLR2 and TLR9 polymorphisms with COPD risk by logistic regression analysis. TLR9-rs352140, TLR2-rs3804100, and TLR2-rs5743705 were related to a lower risk of COPD among Chinese people and the significance still existed after Bonferroni correction. Additionally, rs3804099, rs3804100, and rs352140 were found to be associated with COPD development in different subgroups (males, age ≤ 68 years, smokers, BMI < 24 kg/m2, and acute exacerbation). Our findings indicated that TLR9 and TLR2 polymorphisms had protective effects on the development of COPD among Chinese people.